In the chemical synthesis of organic compounds having amine functional groups, it is often advantageous to block primary or secondary amino groups via conversion to a less reactive group such as a urethane, amide, or sulfonamide. Protection of amine sites enables modifications to be made to other parts of the molecule without interference from the reactive amino groups. Reagents such as Cbz-Cl (Benzyl chloroformate, a.k.a. carbobenzyloxy chloride), or the anhydrides of Boc (t-Butyloxycarbonyl) and Fmoc (9-flourenylmethyloxycarbonyl), etc. are traditionally employed for this purpose in synthesis. However, the resulting urethanes suffer from the limitation of being too easily deprotected. An alternative form of protected amines RR′NH are the sulfonamides RR′NSO2R″, typically formed by treatment of the amines with aryl or alkyl sulfonyl chlorides ClSO2R″. The most common arylsulfonyl group —SO2R″ is p-toluenesulfonyl (or “tosyl”) group, where R″ is the 4-methylphenyl group. As protected amines, sulfonamides are much more stable than the urethanes, but therefore, the corresponding deprotection (i.e. removal of the aryl- or alkylsulfonyl protection groups) to recover the protected amine represents a significant challenge.
Cleavage of sulfonamides to liberate the corresponding primary or secondary amines has traditionally been problematic. The relatively few reports of amine detosylations in the literature suffer from the limitations of poor yields, lack of generality, lack of functional group tolerance, or excessive harshness in terms of reaction conditions. For example, strong acids such as 40% HBr in acetic acid or powerful organic reductants, such as potassium naphthalide or sodium-mercury amalgam, are typically used to perform the detosylation of tolyl-sulfonamides of secondary amines. These harsh reaction conditions can alter or destroy much functionality during a multi-step total synthesis. In addition, both reaction strategies generate significant amounts of potentially hazardous waste byproducts.
Tosyl chloride is a fairly inexpensive compound which is produced on a large scale as a by-product of saccharine synthesis. Its low price makes it a more economical substance for chemical syntheses than the other reagents which may be used for the protection of amino groups. It is a standard procedure to form secondary amines from primary amines through tosylation of the primary amino group. The usual sequence of reactions is as follows:RNH2+TsCl+B→RNHTs+HCl*B  (1)RNHTs+B→BH+RNTs−  (2)RNTs−+R′X→RR′NTs+X−  (3)RR′NTs→RR′NH  (4)
The tosylation of amines (Reaction Step 1) usually proceeds very easily. Here B represents a base, such as triethylamine, excess of the amine, alkali metal carbonate, pyridine, etc. The obtained tosylated amines (toluenesulfonamides, but termed here “tosyl amines” for simplicity) are usually well-behaving substances that easily crystallize, and can be purified by crystallization. Their 1H and 13C NMR spectra typically have the distinct patterns of the tosyl group, which makes their identification easy. Reaction Steps 2 and 3 are often combined in a single synthetic step.
The particular feature of the alkylation of the amines through tosylation is that the tosyl group, while activating the primary amine towards alkylation by enabling it to be deprotonated to form an amide anion, avoids the further alkylation (quaternization) of nitrogen because of the strong electron withdrawing effect of the tosyl group.
A difficulty that often limits the use of tosyl groups for amine synthesis is the last step, the deprotection of the secondary amine. This step frequently becomes a problem because of the very high stability of the sulfonamide group. Typical deprotection procedures include reflux of the tosylamine with concentrated hydrochloric acid, heating to 100° C. in concentrated sulfuric acid, reacting with saturated solution of hydrogen bromide and phenol in acetic acid. Those procedures, including application of strong acids, may easily destroy many groups present in the molecules of the deprotected substance, which severely limits use of the tosylamines in organic synthesis and pharmaceutical industry.
The deprotection of tosylamines can be done by reaction with sodium in liquid ammonia. This procedure, however, includes work with special equipment, such as a liquid ammonia gas tank, cooling equipment, etc., compressed poisonous gases, such as ammonia, and highly flammable metals, such as sodium, which makes the whole procedure cumbersome. Thus, the relatively few reports of secondary amine detosylations in the literature suffer from the limitations of lack of generality, lack of functional group tolerance or excessive harshness in terms of reaction conditions. There is a mild method of detosylation—reaction with sodium amalgam. The drawback of this method is utilization of mercury, a toxic heavy metal. Therefore, there is a need for a simple, fast, and safe detosylation technique which would increase the applicability of the tosylamines in the organic synthesis.